Project Summary: The proposed University of Utah School of Medicine (UUSM) Cooperative Hematology Specialized Core Center (CHSCC) brings together 22 investigators whose research activities are focused on various aspects of iron and heme metabolism and non-malignant hematology. Iron plays an essential role in many biological processes including heme synthesis, oxygen transport, cellular respiration and DNA synthesis. Malregulation of iron homeostasis, either from deficiency or excess, results in disease. Heme is a key component of hemoglobin and other hemoproteins, but heme also plays a regulatory role in a number of metabolic pathways. Disorders of heme biosynthesis are responsible for an important group of human diseases, namely the porphyrias. The proposed Utah Center for Iron and Heme Disorders (CIHD) will support the activities of 22 investigators whose research projects focus on the roles of iron, porphyrins and heme in eukaryotic metabolism. The activities of center members encompass both basic and clinical studies designed to identify disease mechanisms. To accomplish our goals, we propose to provide an Administrative Core and four Biomedical Research Cores. The majority of the cores are already present and have been adjusted to the needs of the CIHD. These include: a Mutation Generation and Detection Core, which provides cutting edge genome editing through CRISPR and TALEN reagents; a Zebrafish Core, in which conditions have been optimized to generate zebrafish with engineered genomes for both gene discovery and genetic and chemical screens; a Metabolomics Core, which provides metabolomic phenotyping and molecular identification; and an Iron and Heme Core, which can assay and quantitate metals, porphyrins, heme biosynthetic enzymes and iron-binding and other proteins. The services provided by these cores will enable individual investigators to: 1) identify the role of genes in hematopoiesis or iron overload; 2) determine the effects of gene modification or mutations on metabolism in cultured cells or biological fluids; and 3) identify on a biochemical level the effect of mutations or treatments on heme synthesis on levels ranging from gene to protein to products. The Administrative Core will provide budgetary and scientific guidance to CIHD activities. Core recharge fees will be used to enhance and expand Core operations. The Pilot & Feasibility (P&F) and Enrichment Programs are designed for trainees and young investigators in the fields of nonmalignant hematology and for senior investigators who wish to enter this field. The 22 members of the CIHD are drawn from both the University of Utah and other institutions, with half of the members belonging to institutions outside of Utah. The goals of the CIHD are to be a national resource for studies involving iron and heme and to inspire the next generation of investigators focused on iron, heme and nonmalignant hematology.